Enhanced stability of novel liquid compositions

ABSTRACT

The present invention relates to compositions of pharmaceutical agents in combination with additional pharmaceutical agents in a mixture of polyethylene glycol, polyvinylpyrrolidone, and propylene glycol and a process of making the compositions.

This application claims the benefit under 35 USC 119(e) of U.S.Provisional Application No. 61/770,988 filed on Feb. 28, 2013, thecontents of which is hereby incorporated by reference in its entirety.

FIELD OF INVENTION

The present invention relates to compositions and a process whereby thecomposition comprises pharmaceutical agents alone or in combination withadditional pharmaceutical agents in a mixture of polyethylene glycol,polyvinylpyrrolidone (PVP) and propylene glycol.

BACKGROUND OF THE INVENTION

Liquid, and especially concentrated liquid, pharmaceutical compositionsoffer several advantages over solid compositions. Liquids are easy toswallow and provide an excellent vehicle for the uniform delivery ofpharmaceutical agents. Moreover, liquids provide a rapid onset ofpharmacologic action, since the composition does not first have todisintegrate and dissolve in the gastrointestinal tract. Likewise,concentrated liquid compositions offer certain distinct advantages, suchas faster onset of efficacy due to the high concentration ofpharmaceutical agents. Consumers prefer a concentrated liquidcomposition due to the ease of dosing, and less volume of doses.

These advantages notwithstanding, it is, however, often difficult toprepare such compositions using the desired pharmaceutical agents. Manypharmaceutical agents are poorly soluble and, therefore, requirerelatively large volumes of solvent for dissolution, resulting inimpractically large doses. Furthermore, the situation becomes even morecomplicated when multiple pharmaceutical agents are involved, andparticularly where the soluble pharmaceutical agent is in combinationwith additional water soluble pharmaceutical agent(s) that may hinderthe efficacy of at least one or more of the pharmaceutical agents andproduce a bitter taste that consumers would be discouraged from using.

Guaifenesin is a well known pharmaceutical agent, classified as anexpectorant, and is sold as tablets or syrups under many brand names.Single-ingredient formulations of guaifenesin are available, and it isalso included in many other over-the-counter cough and cold remedycombinations, usually in conjunction with dextromethorphan and/oracetominophen and/or ephedrine/pseudoephedrine or phenylephrine.Guaifenesin is a component of Robitussin™ DM, Robitussin™ DM MAX,Robitussin™ CF Max and other well known brand names. Generally theconcentration of guaifenesin in most over-the-counter cough medicines isapproximately 100 mg/5 mL liquid to 200 mg/5 mL. As an example, theRobitussin™ CF Max product contains 100 mg/5 mL and Mucinex™ Fast-Max™Severe Congestion and Cough product contains 100 mg guaifenesin/5 mLliquid.

It has been reported in the literature that the aqueous solubility ofguaifenesin, a soluble drug in water, could be significantly reduced inthe presence of salts, sugars, and higher concentrations of cosolvents.See “Solubility of Guaifenesin In The Presence Of Common PharmaceuticalAdditives,” Narasimhan Mani, Pharm Dev Technol 8:385-96. 2003.

Many commercially available over-the-counter liquid cold, cough, flu,fever, and/or allergy preparations contain pseudoephedrine as an activeagent. Although such preparations have been useful, misuse of suchproducts as a starting material for synthesis of illicit substances haslead to the desire to find alternatives that are not suitable for suchillicit synthesis. Phenylephrine is a potential alternative agent.However, phenylephrine is susceptible to degradation. The degradation istypically facilitated in excipient compositions of the type typicallyused with pseudoephedrine.

Accordingly, it would be desirable to have a palatable, stable, liquidcomposition with inhibited precipitation of pharmaceutical agents, suchas guaifenesin, alone or in combination with additional pharmaceuticalagents, such as phenylephrine, in a mixture of polyethylene glycol,polyvinylpyrrolidone and propylene glycol.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to an oral liquidcomposition comprising:

-   -   i.) from about 0.1% to about 20% w/v polyvinylpyrrolidone;    -   ii.) from about 5% to about 70% w/v polyethylene glycol;    -   iii.) from about 1% to about 30% w/v propylene glycol;    -   iv.) from about 1% to 10% w/v guaifenesin; and    -   v.) from about 0.01% to about 1.0% w/v phenylephrine.

In another embodiment, the present invention relates to a liquid oralpharmaceutical composition comprising:

-   -   i.) about 0.2% w/v dextromethorphan;    -   ii.) about 4% w/v guaifenesin;    -   iii.) about 0.1% w/v phenylephrine;    -   iv.) about 10% w/v propylene glycol;    -   v.) about 10% w/v polyethylene glycol; and    -   vi.) about 0.5% w/v polyvinylpyrrolidone.

The composition may be a solution or a suspension. In some embodimentsthe composition may be filled into capsules.

The present invention further relates to a process for preparing an oralliquid composition, comprising the steps of:

-   -   a.) mixing until dissolved from about 0.1% to about 20% w/v of        polyvinylpyrrolidone in an aqueous phase;    -   b.) adding and mixing from about 1% to about 20% w/v of at least        one pharmaceutical agent;    -   c.) subsequently adding and mixing:        -   i.) water;        -   ii.) from about 1% to about 30% w/v of a propylene glycol;        -   iii.) from about 5% to about 70% w/v of a polyethylene            glycol; and    -   d.) subsequently adding and mixing one or more additional        ingredients.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a palatable, stable, oral liquidcomposition with inhibited precipitation of pharmaceutical agents, suchas guaifenesin, in combination with additional pharmaceutical agents,such as phenylephrine, in a mixture of polyethylene glycol,polyvinylpyrrolidone (PVP) and propylene glycol. The composition isparticularly well suited for the relief of cold, cough, flu, fever,headache, pain, body ache, migraine, and allergy symptoms.

The composition of the invention may be a solution or a suspension oralternatively filled into capsules. In solution and suspensionembodiments, the composition comprises guaifenesin and phenylephrine, ina mixture of polyethylene glycol, polyvinylpyrrolidone and propyleneglycol. Optionally, the composition may comprise one or more otheragents.

“Solution” as used herein means a uniform dispersed mixture at molecularor ionic level of one or more pharmaceutical actives (the solute) in oneor more other substances (the solvent). The physical state of thesolution at normal ambient conditions is such that it is readilydispensed from a vessel by pouring.

Consumers show strong preference for lower dose volumes that contain asufficiently high enough concentration of pharmaceutical actives toprovide the desired therapeutic benefit of the active. As a result ofthis effort to meet consumer needs, the compositions of the presentinvention are intended to be dosed in low volumes.

Method for Delivery of the Composition into the Body

The delivery of drugs into the bloodstream by placing a dosage form intothe mouth can be classified into two major subclasses dependent upon thedesired action. In one case where the drug is delivered into the bloodby absorption after swallowing (i.e. from the stomach, small intestineor colon) and in the other case where absorption, or at least thesignificant amount of the absorption occurs through the membranes of theoral cavity either immediately or over extended periods of time when thecompositions are retained in the mouth prior to swallowing. This routeis generally referred to as “buccal” or “oral mucosal” absorption versusthe former route normally referred to as peroral administration ofactives. Peroral administration of actives is by far the most commonlyused in all of medicine, has been well studied, and is explained indetail in: Mayerson, M., Principles of Drug Absorption; Chapter 2 in“Modem Pharmaceutics”, 2nd ed., G. S. Banker and C. T. Rhodes, editors,Marcel Dekker Inc., New York, 1990; herein incorporated by reference.

The preferred route of administration of the present invention isperoral.

All percentages and ratios used herein are by weight per volume (% w/v)and all measurements are at 25° C., unless otherwise indicated.

Liquid Pharmaceutical Compositions

The liquid pharmaceutical compositions of the present invention comprisethe following components, as well as optional components.

Polyethylene Glycol (PEG)

A component of the present compositions is a polyethylene glycol.Polyethylene glycols generally are clear, viscous liquids or whitesolids which are soluble in water and many organic solvents.Polyethylene glycols are generally bitter tasting, especially the lowermolecular weight glycols, which are usually the most effective glycolsin solubilizing pharmaceutical agents. These polymers correspond to thegeneral formula:H—(O—CH₂—CH₂)_(n)—OHwhere n is greater than or equal to 4.

Polyethylene glycols are described in G. M. Powell, III in Handbook ofWater-Soluble Gums & Resins, R. L. Davidson, Ed. (McGraw-Hill, New York,1980) pp. 18/1-18/31, this reference being incorporated herein byreference in its entirety. Polyethylene glycols, which are also known as“PEGs” or “polyoxyethylenes”, are designated by both their averagemolecular weight range and their average “n” value as in the abovedesignated formula. For example, polyethylene glycol 400, which is alsoknown by the CTFA designation, PEG-8, has an average molecular weightrange from 380-420 and an average value of n between 8.2 and 9.1. SeeCTFA Cosmetic Ingredient Dictionary, Third Edition (1982), pp. 201-203;and The Merck Index, Tenth Edition, entry 7441, p. 1092 (1983); thesetwo references being incorporated herein by reference in their entirety.

The polyethylene glycols useful herein are mixtures of those which areliquids at room temperature or have a melting point slightly thereabove. Preferred mixtures include those polyethylene glycols having amolecular weight range of from about 300 to about 1500 and correspondingn values of from about 6 to about 30. More preferred are those ofpolyethylene glycols having a molecular weight range of from about 400to about 800 and corresponding n values of n from about 8 to about 16.Most preferred are those polyethylene glycols having a molecular weightrange of from about 400 to about 600 and corresponding n values fromabout 8 to about 12. Liquid and low-melting polyethylene glycols arecommercially available from multiple sources, including Sasol GmbH ofHamburg, Germany and Union Carbide (Danbury, Conn.) under the Carbowax™trademark. See “Carbowax™ Polyethylene Glycols”, Union Carbide TechnicalBulletin f-4772M-ICD 11/86-20M, this reference being incorporated hereinby reference in its entirety.

The oral liquid compositions of the present invention comprise fromabout 5% to about 70% w/v polyethylene glycol, more preferably fromabout 7% to about 30% w/v, and most preferably about 10% w/vpolyethylene glycol. The process for making the oral liquid compositionsof the present invention include the addition of polyethylene glycolwithin the stated ranges above.

Polyvinylpyrrolidone (PVP)

A component of the present compositions is polyvinylpyrrolidone, whichis a polymer of N-vinyl-2-pyrrolidone.

Polyvinylpyrrolidones are described in L. Blecher et al. in Handbook ofWater-Soluble Gums & Resins, R. L. Davidson, Ed. (McGraw-Hill, New York,1980) pp. 21/1-21/21, this reference being incorporated herein byreference in its entirety. Polyvinylpyrrolidone has different solubilitycharacteristics based on its polymeric structure. Long-chainpolyvinylpyrrolidone, which is also known as povidone, has goodsolubility in water and a number of organic solvents. Cross-linkedpolyvinylpyrrolidone, which is also known as crospovidone, is insolublein virtually all common solvents. Both the soluble and insoluble formsof polyvinylpyrrolidone are commercially available from GAF ChemicalsCompany (Wayne, N.J.) under the Plasdone™ and Polyplasdone™ trademarks,respectively, and from BASF Aktiengesellschaft (Ludwigshafen, Germany)under the Kollidon™ trademark. Soluble forms of polyvinylpyrrolidoneinclude Plasdone™ K-25, Plasdone™ K-26/28, Plasdone™ K-29/32, PlasdoneVC-15, Plasdone™ C-30, Plasdone™ C-90, Kollidon™ 12 PF, Kollidon™ 17 PF,Kollidon™ 25, Kollidon™ 30, and Kollidon™ 90 Grades,Polyvinylpyrrolidone for the Pharmaceutical Industry”, BASF TechnicalBulletin MEF 129e, Register 2, May 1986 (Bn); these references beingincorporated herein by reference in their entirety.

The soluble forms of polyvinylpyrrolidone are preferred for use in thepresent invention. Preferred are soluble polyvinylpyrrolidones having anaverage molecular weight in the range of from about 2,000 to about1,500,000; more preferred are those having an average molecular weightin the range of about 1,000,000 to about 1,500,000. Moreover, mixturesof two or more soluble polyvinylpyrrolidones of different averagemolecular weight can be employed. Kollidon™ 90 grade is the preferredgrade of polyvinylpyrrolidone utilized in the present invention.

The oral liquid compositions of the present invention comprise fromabout 0.1% to about 20% w/v of a soluble polyvinylpyrrolidone, morepreferably from about 0.20% to about 2% w/v, and most preferably about0.5% w/v polyvinylpyrrolidone. The process for making the oral liquidcompositions of the present invention include the addition ofpolyvinylpyrrolidone within the stated ranges above.

Preferably, the ratio of the total amount of polyethylene glycol topolyvinylpyrrolidone should be about 20:1.

Propylene Glycol

A component of the present invention is propylene glycol, which isrepresented by the formula:C₃H₈O₂ or HO—CH₂—CHOH—CH₃is well known in the art for its solvent and/or humectant properties. Acolorless and viscous liquid, propylene glycol is miscible with water,alcohols and many organic solvents. Propylene glycol has a bitter taste.Propylene glycol is described in Hawley's Condensed Chemical Dictionary,pp. 970-971, (Revised by Richard J. Lewis, Sr., 12th ed. 1993, hereinincorporated by reference). Propylene glycol suitable for use in thepresent invention is obtainable from any number of suppliers, DowChemical being one.

The oral liquid compositions of the present invention comprise fromabout 1% to about 30% w/v of propylene glycol, more preferably fromabout 5% to about 20% w/v, and most preferably about 10% w/v ofpropylene glycol. The process for making the oral liquid compositions ofthe present invention include the addition of propylene glycol withinthe stated ranges above.

Pharmaceutical Agents

The compositions of the instant invention contain at least onepharmaceutical agent as an essential component. In general, thesepharmaceutical agents have a solubility less than or equal to about 4%w/v in water at 25° C. Useful classes of pharmaceutically-active agentswhich can be incorporated into the present compositions includeanalgesics, anti-inflammatory agents, anti-pyretics, calcium channelblockers, beta-blockers, antibacterials, antidepressants,anti-diabetics, anti-emetics, antihistamines, cerebral stimulants,sedatives, anti-parasitics, expectorants, diuretics, decongestants,antitussives, muscle relaxants, anti-Parkinsonian agents,bronchodilators, cardiotonics, antibiotics, antivirals, nutritionalsupplements (such as vitamins, minerals, fatty acids, amino acids, andthe like), and mixtures thereof. Pharmaceutical agents selected from thenon-narcotic analgesics/nonsteroidal anti-inflammatory drugs areespecially useful in the present invention. Examples of such drugs aredisclosed in U.S. Pat. No. 4,522,828, to Sunshine et al., issued Jun.11, 1985, incorporated herein by reference in its entirety.

Examples of preferred pharmaceutical agents useful in the presentinvention include, but are not limited to, acetaminophen,acetylsalicylic acid, dextromethorphan, ibuprofen, fenbuprofen,fenoprofert, flurbiprofen, guaifenesin, phenylephrine, indomethacin,ketoprofen, naproxen, their pharmaceutically-acceptable salts, andmixtures thereof. Guaifenesin is especially preferred for use in thepresent invention.

Guaifenesin, which is represented by the formula: C₁₀H₁₄O, includeshydrophilic end groups which are soluble in water and hydrophobic endgroups which limit water solubility. Guaifenesin may be used in thecomposition in amounts of about 0.4% w/v to about 6% w/v and preferablyin amounts of about 2% w/v to about 4% w/v. Guaifenesin suitable for usein the present invention is obtainable from any number of suppliers,Rhodia Operations SAS of Aubervilliers, France being one.

Guaifenesin, a soluble pharmaceutical agent in water, has a solubilityof approximately 4% by weight in water at 25° C. However, it is wellknown that saturated solutions are prone to precipitate at coldtemperatures. Precipitation of guaifenesin out of solution in aconcentrated cold and cough oral liquid composition, particularly at lowtemperatures, is a problem for many manufacturers and distributors. Manyconsumer complaints regarding the guaifenesin precipitation issue incommercially available compositions led to the research and developmentof the present invention. Further complicating the issue, ingredientchanges to the composition affected the chemical stability of additionalpharmaceutical agents in the composition, such as phenylephrine HCl.

Preferably the phenylephrine is in a salt form. Suitable salt formsinclude, but are not limited to, phenylephrine hydrochloride (HCl),hydrobromide (HBr), bitartarate and tannate salts. Preferably,phenylephrine is used in an amount of about 0.001% w/v to about 2.5%w/v.

Phenylephrine suitable for inclusion in the present invention isavailable from multiple commercial suppliers, such as BoehringerIngerheim of Ridgefield, Conn.

Herein percent w/v means a percentage determined by the followingformula:w/v %=Weight of component (in grams)/Volume of composition (inmilliliters)×100.

Accordingly, for example, 1% w/v phenylephrine means 1 gram ofphenylephrine in 100 ml of the oral liquid composition.

While a liquid composition comprising polyethylene glycol, propyleneglycol, polyvinylpyrrolidone, along with guaifenesin and phenylephrinemay seem to be a fairly straight forward liquid composition, theinteractions between the agents themselves and with additionalingredients complicates the solubility of the agents in the liquidcomposition, the stability of the agents, and the taste to the consumer.

Polyethylene glycol, particularly PEG™ 400, and propylene glycol assistin the inhibition of the precipitation of guaifenesin but are bittertasting and contain aldehydic impurities, such as formaldehyde andacetaldehyde, that degrade the phenylephrine.

Polyvinylpyrrolidone is considered a very effective agent for inhibitingprecipitation of highly concentrated pharmaceutical agents in liquidsand liquid filled soft gels. It is disclosed in U.S. Pat. No. 5,505,961,assigned to R. P. Scherer, that polyvinylpyrrolidone is essential forinhibiting crystallization in liquid-filled soft gel capsules containinghigh concentrations of acetominophen. PCT Application WO 93/00072,Coapman, discloses a process for solubilizing pharmaceutical activesconsidered difficult to solubilize. This process requirespolyvinylpyrrolidone to aid in solubilizing the active agent andpreventing precipitation. Similar limitations are disclosed for theacetaminophen solutions described in PCT Application WO 95/23595, byDhabhar, wherein polyvinylpyrrolidone is disclosed as an essentialcomponent of the compositions that are the subject matter of the Dhabharpatent. However, polyvinylpyrrolidone, while inhibiting theprecipitation of guaifenesin, also may contain aldehydic impuritieswhich degrade the phenylephrine. Polyvinylpyrrolidone can also assist inmasking the bitter taste of the glycols.

Preferably, the ratio of the total amount of polyvinylpyrrolidone toguaifenesin should be about 1:2 in the absence of phenylephrine in thecompositions of the present invention.

In the presence of phenylephrine, the ratio of the total amount ofpolyvinylpyrrolidone to guaifenesin should be about 1:8 in thecompositions of present invention.

Additional Pharmaceutical Agents and Ingredients

An artificial sweetener may be provided to improve palatability. Anartificial sweetener is preferred for use as a sweetener to the use ofconventional sugar sweeteners as the inventors believe, without wishingto be held to the theory that conventional sugars may contribute to thedegradation of phenylephrine in aqueous based compositions. Suitableartificial sweeteners, include but are not limited to sucralose,saccharine salts, cyclamates, acesulfame K, dipeptide based sweeteners,aspartame and mixtures thereof. Sucralose, which is a high intensitysweetener, is particularly well suited for use in the composition.Sucralose may be used in an amount of about 0.01% to about 0.4% w/v, forexample. The appropriate amount of artificial sweetener depends onproperties and sweetness intensity of the artificial sweetener andtarget organoleptic properties of the composition. One skilled in theart is familiar with the characteristics of sweeteners and methods fordetermining amount of sweetener to be used.

Optionally, glycerin and sorbitol may be used in solution and suspensionembodiments of the composition for taste masking. However glycerin andsorbitol contain aldehydic impurities which contribute to thedegradation of phenylephrine. In one embodiment the composition containsmore glycerin than sorbitol. The inventors believe, without wishing tobe bound to the theory, that reduced amounts of sorbitol facilitatestability of the phenylephrine. The composition may contain up to 45%w/v glycerin and up to about 50% w/v sorbitol. In exemplary embodimentswith reduced sorbitol amounts, the composition may contain about 18% toabout 30% w/v glycerin and about 3% to about 25% w/v sorbitol. Hereinthe amounts of sorbitol and glycerin are the amounts of standardcommercial preparations of sorbitol and glycerin. Commercial sorbitol(as obtained from SPI Polyols, 321 Cherry Lane New Castle, Del. 19720,or Roquette Freves 62080 Lestrew, France, for example) is an aqueousbased composition that is 70% sorbitol. Commercial glycerin (as obtainedfrom Dow Chemical Co., 2030 Dow Center, Midland, Mich. 48674, orLyondell, 1221 McKinney St., Houston, Tex. 77253, for example) is 96percent glycerin. One skilled in the art is familiar with thesecommercial preparations and methods of adjusting amounts should adifferent glycerin preparation (such as, for example, a 99% glycerin) ora different sorbitol preparation be used.

The composition may contain one or more additional pharmaceutical agents(also referred to as “active(s)”, “active agent(s)”, “agents”,“therapeutic agent(s)”, “drug(s)”). Further, the term pharmaceuticalagent may refer to a single species of agent or a plurality of speciesof agents (e.g., the total number of agents in the compositions may begreater than 3). For embodiments of the composition that are solutions,any additional agent should be water soluble. A water-solublepharmaceutical agent means a pharmaceutical agent indicated to besoluble in water by the Merck Index. Additional agents in suspensionembodiments may be water soluble, slightly soluble in water, orinsoluble in an aqueous medium.

Suitable additional pharmaceutical agents include analgesics,decongestants, expectorants, anti-tussives, antipyretics,anti-inflammatory agents, cough suppressants and antihistamines.

Antihistamines useful in the practice of the present invention (alongwith their preferred salt form) include, but are not limited to,chlorpheniramine (maleate), brompheniramine (maleate);dexchlorpheniramine (maleate), dexbrompheniramine (maleate),triprolidine (HCl), diphenhydramine (HCl, citrate), doxylamine(succinate), tripelenamine (HCl), cyproheptatine (HCl), chlorcyclizine(HCl), bromodiphenhydramine (HCl), phenindamine(tartrate), pyrilamine(maleate, tannate), azatadine (maleate); acrivastine, astemizole,azelastine, cetirizine, ebastine, fexofenadine, ketotifen, carbinoxamine(maleate), desloratadine, loratadine, pheniramine maleate, thonzylamine(HCl), mizolastine and terfenadine.

Antitussives useful in the practice of the present invention (along withtheir preferred salt form) include, but are not limited to,chlophendianol, caramiphen (ediylate), dextromethorphan (HBr),diphenhydramine (citrate, HCl), codeine (phosphate, sulfate) andhydrocodone.

Decongestants useful in the practice of the invention (along with theirpreferred salt form) include, but are not limited to, pseudoephedrine(HCl, sulfate), ephedrine (HCl, sulfate), phenylephrine (bitartarate,tannate, HBr, HCl), and phenylpropenolamine (HCl).

Expectorants which may be used in the practice of the invention (alongwith their preferred salt form) include but are not limited to terpinhydrate, guaifenesin (glycerol, guaiacolate), potassium (iodide,citrate) and potassium guaicolsulfonate.

Non-steroidal anti-inflammatory drugs (NSAIDS) which may be used in thepractice of the invention include, but are not limited to, propionicacid derivatives such as ibuprofen, naproxen, ketoprofen, flurbiprofen,fenoprofen, suprofen, fluprofen and fenbufen; acetic acid derivativessuch as tolmetin sodium, zomepirac, sulindac, and indomethacin; fenamicacid derivatives such as mefenamic acid and meclofenamate sodium;biphenyl carboxylic acid derivatives such as diflunisal and flufenisaland oxicams such as piroxicam, sudoxicam and isoxicam.

Cox 2 inhibitors which may be used in the practice of the inventioninclude, but are not limited to, celecoxib, rofecoxib and valdecoxib.

Analgesics which may be used in the practice of the invention includebut are not limited to aspirin, acetominophen, phenacetin and salicylatesalts.

Examples of substantially insoluble pharmaceutical agents that may besuspended in the suspending system of suspension embodiments include,but are not limited to, nabumetone, glimepiride, diclofenac, piroxicamand meloxican.

Of the pharmaceutically agent compounds described above which may beincluded in addition to guaifenesin and phenylephrine in thecomposition, those which are particularly preferred are set forth belowalong with preferred ranges for their inclusion into the claimedpharmaceutical composition.

Chlorpheniramine may be used in the pharmaceutical composition inamounts between about 0.01% w/v and about 0.05% w/v. Preferablychlorpheniramine, when used in the pharmaceutical composition, ispresent in the amount of about 0.01% w/v to 0.03% w/v.

Chlorpheniramine maleate may be used in the pharmaceutical composition,preferably in the amount of about 0.01% w/v to about 0.03% w/v.

Brompheniramine maleate may be used in the pharmaceutical composition,preferably in the amount of about 0.01% w/v to about 0.03% w/v.

Dextromethorphan HBr may be used in the pharmaceutical composition,preferably in the amount of about 0.05% w/v to about 0.250% w/v.

Chlophendianol may be used in the composition in amounts of about 0.1%w/v to about 1% w/v and preferably in amounts of about 0.25% w/v toabout 0.5% w/v.

Diphenhydramine may be used in the composition in amounts of about 0.2%w/v to about 2% w/v and preferably in amounts of about 0.5% w/v to about1% w/v.

Brompheniramine may be used in the composition in amounts of about0.016% w/v to about 0.16% w/v and preferably in amounts of about 0.02%w/v to about 0.08% w/v.

Loratadine may be used in the composition in amounts of about 0.02% w/vto about 0.4% w/v and preferably in amounts of about 0.1% w/v to about0.2% w/v.

Aspirin may be used in the composition in amounts of about 0.8% w/v toabout 13% w/v and preferably in amounts of about 3.2% w/v to about 7.2%w/v.

Doxylamine may be used in the composition in amounts of about 0.1% w/vto about 1% w/v and preferably in amounts about 0.25% w/v to about 0.5%w/v.

Acetaminophen may be used in the composition in amounts of about 0.12%w/v to about 13% w/v and preferably in amounts of about 1.2% w/v toabout 4% w/v.

Amounts of pharmaceutically agent compounds incorporated areconventional dosages known to those skilled in the art. Further, forpharmaceutical compositions intended for use in the United States,amounts of pharmaceutical agents are preferably in compliance withapplicable FDA regulations regarding dosage of such compounds.

The pharmaceutically agent compounds are preferably, but not limited to,a compendial grade such as, for example, N.F. (National Formulary) orU.S.P. (United States Pharmacopeia) grade.

Excipients known by those skilled in the art may be useful in thepractice of the present invention. Such excipients may include, but arenot limited to, humectants such as glycerin, sweeteners, defoamingagents, buffers, electrolytes, preservatives such as sodium benzoate anddisodium edetate, antioxidants, taste masking agents and variousflavoring and coloring agents, for example. Optionally, some embodimentsmay include viscosity modifiers such as, for example, glycerin, xanthan,and/or povidone; and/or densifiers such as, for example, sorbitol orglycerin.

Examples of suitable flavoring agents include, but are not limited to,natural and artificial flavors such as mints (i.e., peppermint, etc.),menthol, chocolate, artificial chocolate, bubblegum, both artificial andnatural fruit flavors (i.e., cherry, grape, orange, strawberry, etc.)and combinations of two or more thereof. It is preferable to avoidflavoring agents which have aldehyde functional groups (e.g. usenon-aldehyde containing flavorants is preferred). Flavoring agents aregenerally provided as a minor component of the composition in amountseffective to provide palatable flavor to the compositions. Typically,flavoring agents are present in amounts in the range of about 0% w/v toabout 5% w/v in the composition.

Optionally, an antioxidant may be used in the composition. Propylgallate is exemplary of an antioxidant that is suitable for use in thecomposition.

Preservatives useful in the present invention include but are notlimited to sodium benzoate, sorbates, such as potassium sorbate, saltsof edetate (also known as salts of ethylenediaminetetraacetic acid orEDTA, such as disodium edetate), benzaldionium chloride and parabens(such as methyl, ethyl, propyl, and butyl p-hydroxybenzoic acid esters).Preservatives listed above are exemplary, but each preservative must beevaluated on an experimental basis, in each formulation to assurecompatibility and efficacy of the preservative. Methods for evaluatingthe efficacy of preservatives in pharmaceutical formulations are knownto those skilled in the art. Sodium benzoate and disodium edetate arethe presently preferred preservative ingredients.

Preservatives are generally present in amounts of up to one gram per 100ml of the pharmaceutical composition. Preferably the preservatives arepresent in amounts in the range of from about 0.01% w/v to about 0.4%w/v of the composition. Typically, the preservative sodium benzoatewould be present in the range of about 0.1% w/v to about 0.2% w/v of thecomposition, for example. Sodium benzoate was used in a concentration ofabout 0.1% w/v in an exemplary embodiment of the composition.

Sodium citrate is exemplary of a buffering agent which may be used inthe composition. It is preferable to buffer the composition to maintainthe pH in the range from about pH 2 to about pH 5. More preferably, thepH is maintained in the range from about 3.2 to about 3.8. Mostpreferably, the pH is about 3.5.

Coloring agents may also be incorporated in the pharmaceuticalcomposition to provide an appealing color to the composition. Thecoloring agents should be selected to avoid chemical incompatibilitieswith other ingredients in the composition. Suitable coloring agents arewell known to those skilled in the art.

In some embodiments, particularly suspension embodiments, a surfacemodifying agent, such as a surfactant, may be used in the pharmaceuticalcomposition to modify the surface of the suspended components. Suchsurface modification is believed to facilitate diminished irreversibleaggregation of the suspended particles. The surfactant may be an ionicor non-ionic surfactant or mixtures thereof. Exemplary surfactantsinclude but are not limited to polysorbates (tweens), Span™, togats,lecithin, polyoxyethylene-polyoxypropylene block copolymers and mediumchain mono/di-glycerides.

Typically, suspension embodiments will further comprise a viscositymodifying agents. Suitable viscosity modifying agents include but arenot limited to chitosan, xanthan, povidone, hydroxpropylmethylcellulose(HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC),glactomannons such as guar, konjac, locust bean gum and mamman, forexample, microcrystalline cellulose and combinations thereof.

Xanthan gums suitable for use in the present invention are highmolecular weight polysaccharides such as the xanthan gum produced byXanthamonas capestris, for example. Xanthan gum is an article ofcommerce and is available, for example, from manufacturers such as:Rhodia, Inc. under the brand name Rhodigel™ and from Kelco™, a divisionof Merck. Rhodigel™ 80 Pharm Grade is exemplary of one specificcommercial product suitable for use in the practice of the invention.

Microcrystalline cellulose is commercially available from suppliers suchas FMC (1735 Market Street, Philadelphia, Pa. 19103) under the tradenameAvicelV™.

The amount of viscosity modifier used depends on the desired “thickness”of the composition and the type viscosity modifier used. Combinations ofviscosity modifiers may be employed. For example, in an exemplaryembodiment with a viscosity of about 1500 to about 4500 cps, up to about1.0% w/v xanthan gum may be used and up to about 3.0% w/vmicrocrystalline cellulose may be used as a viscosity modifier.

It is preferable to avoid viscosity modifiers with a significantpresence of negatively charged moieties or moieties with propensity toionize to a negative charge if the structure of the modifier is suchthat the negatively charged moiety is readily available for reaction.

Suspensions are useful for preparing compositions comprising agents thatare substantially insoluble in water. In suspension embodiments thephenylephrine is dissolved in the aqueous medium. The composition maycontain one or more second agent agents dissolved in the aqueous mediumand/or one or more substantially water insoluble second agent agents maybe suspended in the composition. For the suspension embodiments, it ispreferable that both the suspended substantially insoluble agentingredients and any soluble agent ingredients dissolved in the aqueousmedium, are distributed to form a substantially homogeneous distributionof agent ingredients in the pharmaceutical composition.

Exemplary pharmaceutical agents that are substantially insoluble in theaqueous composition and would be expected to form suspension include butare not limited to ibuprofen, ketoprofen, naproxen, celecoxib,rofecoxib, valdecoxib, nabumetone, glimepiride, diclofenac, piroxicamand meloxican. For pharmaceutical agents not specified on this list apharmaceutical agent substantially insoluble in the aqueous compositionmeans a pharmaceutical agent designated as relatively insoluble orinsoluble in water by the Merck Index.

Typically, solution and suspension forms of the composition are providedto a patient in need of treatment in a dosage unit of 10 mL althoughother dosage units may be likewise suitable. The dosage unit may beprovided as a single dosage unit or multiples thereof, based on age,weight and other health parameters determined by a physician to berelevant.

Soft Gelatin Capsules

The solubilized pharmaceutical compositions of the present invention canbe encapsulated within any conventional soft gelatin shell that iscapable of substantially containing the composition for a reasonableperiod of time. Optionally, the soft gelatin shell is essentiallytransparent so as to enhance the aesthetic qualities of the capsule. Thesoft gelatin shells may comprise well known essential components, suchas gelatin, plasticizer and water as well as optional components such asdescribed in U.S. Pat. No. 5,484,606, issued to Dhabhar on Jun. 16,1996, herein incorporated by reference in its entirety.

Solubility

Because the resultant concentrated oral liquid composition (or fill) isa saturated solution of the soluble pharmaceutical agent(s), there is atendency for the dissolved soluble pharmaceutical agent(s) toprecipitate out of solution, particularly at lower temperatures, such as4° C. and below.

Several approaches to solve the issues of guaifenesin precipitation andthe reduced stability of phenylephrine HCl were undertaken, but failedto cure the problems.

Viscosity modifications were explored but the resultant compositionswith improved cold temperature stability could not be considered viablecommercial compositions due to their unpalatable viscosity.

Several materials for use as precipitation inhibitors were considered,including two grades of poloxamer and several grades ofpolyvinylpyrrolidone. However, published prior art, such as literatureand patents, teaches away from using polyvinylpyrrolidone withphenylephrine because polyvinylpyrrolidone comprises acetaldehyde as abyproduct of the manufacture. Aldehydes, especially formaldehyde andacetaldehyde, are known to react with phenylephrine HCl and degrade thestability of phenylephrine HCl. Formaldehyde is also present inpolyvinylpyrrolidone and polyethylene glycol. The major phenylephrinedegradants are formed by reactions with aldehydes. Specifically,phenylephrine reacts with formaldehyde and acetaldehyde to formisoquinoline compounds.

A pre-formulation tri-modal solubility experiment to determine thepreferred concentrations of polyethylene glycol, propylene glycol toinhibit the guaifenesin precipitation was performed using various levelsof co-solvents, such as polyethylene glycol, propylene glycol, andethanol. For the present invention, ethanol is not a preferredingredient due to manufacturing and commercial marketing purposes andthus the ethanol experiments were terminated. It was discovered thatpreferred concentrations of propylene glycol and polyethylene glycol tobe from about 5% w/v to about 20% w/v each, more preferably about 10% toabout 15% w/v each. Thus, additional formulation work was necessary,including the use of glycerin and polyvinylpyrrolidone. Glycerin did notassist in solubilization of guaifenesin but the addition ofpolyvinylpyrrolidone assisted in inhibiting the precipitation ofguaifenesin in cold temperatures (4° C. and −20° C.), as shown inExamples below. Applicants then proceed to conduct experimentation onthe compositions for both solubility and stability in the Examplesbelow.

Once the guaifenesin solubility issues, the next issue was the chemicalstability of the phenylephrine HCl. A cation exchange high performanceliquid chromatography (HPLC) assay was used for analytical calculationof the % phenylephrine HCl, and the total unspecified degradants relatedto phenylephrine HCl. Table 2 comprises the average value calculatedfrom data points collected from each sample composition tested. Therespective data points are disclosed in the Examples below.

Due to storage, shipping and other commercial demands, stability andsolubility time periods should be as long as possible, preferably atleast 12 days, more preferably at least 14 days.

The term “visible” in the present invention means observable,detectable, or able to be seen by the naked eye. The term “visibly free”in the present invention means not observable, not detectable, or unseenby the naked eye.

Although Composition 2 had the longest time period of 22 days with novisible guaifenesin precipitation (see Table 1), the average amount ofphenylephrine degradants was higher than the other compositions (seeTable 2). The amount of phenylephrine degradants was observed toincrease when the concentration of polyvinylpyrrolidone was increased(see Table 2).

Customary industry acceptable levels of phenylephrine degradants areabout 8%. Levels of phenylephrine HCl degradation were observed in the2% w/v polyvinylpyrrolidone prototypes (Composition 2 in Example 2), asdiscussed below and exemplified in Table 2. Given that the amount ofimpurities in the raw material is variable, Applicants decided toformulate the product with the least amount of polyvinylpyrrolidone toavoid negative impact on the phenylephrine HCl stability. Various levelsof polyvinylpyrrolidone were experimented with, ranging from about 0% toabout 4% w/v. After much experimentation, the preferred concentration ofpolyvinylpyrrolidone was determined to be about 0.5% w/v.

Composition 4, comprising about 0.5% w/v polyvinylpyrrolidone, about 10%w/v polyethylene glycol and about 10% w/v propylene glycol, remainedphysically stable, (e.g. all agents remain in solution) for at least 62days at 4° C. and for 14 days at −20° C. Composition 4 in Table 1 metthe highly preferred 2-week stability minimum sought by commercialstandards.

Processes

Manufacturing difficulties arise when adding large amounts ofpharmaceutical agent(s) and polyvinylpyrrolidone to an aqueous solution.Applicants' innovative approach was implemented using an inlinehigh-shear mixer, preferably a Silverson Flashbend™ (FLB30).

The compositions of the present invention are prepared by simple mixing.The ingredients are mixed in a vessel equipped with a mechanical stirrer(e.g., a Lightnin mixer), the vessel calibrated and marked to designatethe final volume. The polyvinylpyrrolidone, preferably Povidone™ K-90,was initially dispersed through an inline high shear mixer (SilversonFlashbend™ (FLB30)) into the vessel with a predetermined amount ofwater. The guaifenesin was then added and dissolved in the solution,followed by an aliquot of water substantially less than the target finalvolume. The propylene glycol is added next with mixing, and then thepolyethylene glycol is added with mixing. The additional ingredients areadded either sequentially or pre-mixed with other ingredients and thenadded under manufacturing processes well known in the medicinal liquidmedication art. Uniform mixing is determined by well known standards,such as stabilized refractive index monitoring system. Colorants may beadded directly or premixed with a small amount of water prior toaddition to the main vessel. After all other ingredients are added andmixed sufficiently to dissolve, water is added to bring the total volumeof the composition to the predetermined final volume and mixing iscontinued for approximately thirty minutes for a total mixing time ofabout 4 hours.

EXAMPLES

The following examples further describe and demonstrate embodimentswithin the scope of the present invention. The examples are given solelyfor the purpose of illustration and are not to be construed aslimitations of the present invention, as many variations thereof arepossible without departing from the spirit and scope of the invention.

Sample compositions were placed in a refrigerator (4° C.) and a freezer(−20° C.) and monitored for visible precipitation once per day. Table 1illustrates the number of days with no visible precipitation ofguaifenesin for the present compositions or, in other words, wherein thecompositions are visually free of guaifenesin precipitation at 4° C. andat −20° C.

The following examples illustrate the effect of the interaction betweenguaifenesin, phenylephrine, and the various amounts ofpolyvinylpyrrolidone. Variability of impurities in the agents andingredients used in the different compositions were not analyzed.

Example 1

Composition 1 comprises 0% w/v polyvinylpyrrolidone, about 10% w/vpolyethylene glycol and about 10% w/v propylene glycol. Guaifenesinprecipitation was not visible to the naked eye for at 11 days at −20° C.and for 50 days at 4° C. (See Table 1).

Chemical stability tests to determine the degradation of phenylephrinewere not conducted on Composition 1.

Composition 1 Amount (% w/v) Dextromethorphan HBr 0.20% Guaifenesin4.00% Phenylephrine HCl 0.10% Propylene Glycol 10.00% PolyethyleneGlycol 10.00% Polyvinylpyrrolidone (K-90) 0.00% Citric Acid 0.90%Xanthum Gum 0.10% Menthol 0.02% Glycerin 24.07% FD&C Red #40 0.01%Flavorant 0.80% Sodium Benzoate 0.10% Sodium Citrate 0.20% Sorbitol20.00% Sucralose 0.20% Water q.s. “q.s.” is an abbreviation for theLatin term “quantum satis” or “sufficient quantity”Method

Composition 1 is prepared by simple mixing. The ingredients are mixed ina vessel equipped with a mechanical stirrer (e.g., a Lightnin mixer),the vessel calibrated and marked to designate the final volume. Apredetermined amount of water is added into the vessel. The guaifenesinis then added and dissolved in the solution, followed by an aliquot ofwater substantially less than the target final volume. The propyleneglycol is added next with mixing, and then the polyethylene glycol isadded with mixing. The additional ingredients are added eithersequentially or pre-mixed with other ingredients and then added undermanufacturing processes well known in the medicinal liquid medicationart. Uniform mixing is determined by well known standards, such asstabilized refractive index monitoring system. Colorants may be addeddirectly or premixed with a small amount of water prior to addition tothe main vessel. After all other ingredients are added and mixedsufficiently to dissolve, water is added to bring the total volume ofthe composition to the predetermined final volume and mixing iscontinued for approximately 2 hours.

Example 2

Composition 2 comprises about 2% w/v polyvinylpyrrolidone, about 10% w/vpolyethylene glycol and about 10% w/v propylene glycol. Guaifenesinprecipitation was not visible to the naked eye for about 22 days at −20°C. and for at least 62 days at 4° C. Applicants terminated their visualinspection after 62 days.

Applicants conducted two stability tests over a 3 month time period at40° C. and 75% relative humidity on two identically prepareddevelopmental samples of Composition 2. As shown in Table 2, the averagedegradation of the phenylephrine was observed to be about 3% totalunspecified phenylephrine degradants, calculated from data in a rangefrom about 1.97% to about 4.11%, and about 6% loss of phenylephrine,calculated from data in a range from about 5.28% to about 7.20% (seeComposition 2 in Table 2).

Composition 2 Amount (% w/v) Dextromethorphan HBr 0.20% Guaifenesin4.00% Phenylephrine HCl 0.10% Propylene Glycol 10.00% PolyethyleneGlycol 10.00% Polyvinylpyrrolidone (K-90) 2.00% Citric Acid 0.90%Xanthum Gum 0.10% Menthol 0.02% Glycerin 24.07% FD&C Red #40 0.01%Flavorant 0.80% Sodium Benzoate 0.10% Sodium Citrate 0.20% Sorbitol20.00% Sucralose 0.20% Water q.s.

Composition 2 is prepared by simple mixing. The ingredients are mixed ina vessel equipped with a mechanical stirrer (e.g., a Lightnin mixer),the vessel calibrated and marked to designate the final volume. Thepolyvinylpyrrolidone was initially poured through an inline high shearmixer into the vessel with a predetermined amount of water. Theguaifenesin was then added and dissolved in the solution, followed by analiquot of water substantially less than the target final volume. Thepropylene glycol was added next with mixing, and then the polyethyleneglycol with mixing. The other ingredients are added sequentially withmixing. Colorants may be added directly or premixed with a small amountof water prior to addition to the main vessel. After all otheringredients are added and mixed sufficiently to dissolve, water is addedto bring the total volume of the composition to the predetermined finalvolume and mixing is continued for approximately 2 hours.

Example 3

Composition 3 comprises about 1% w/v polyvinylpyrrolidone, about 10% w/vpolyethylene glycol and about 10% w/v propylene glycol. Guaifenesinprecipitation was not visible to the naked eye for about 14 days at −20°C. and about 45 days at 4° C. Applicants terminated their visualinspection after 45 days.

Applicants conducted two stability tests over a 3 month time period at40° C. and 75% relative humidity on two identically prepared samples ofComposition 3. As shown in Table 2, the average degradation of thephenylephrine was observed to be about 2.27% total unspecifiedphenylephrine degradants, calculated from data in a range from about1.99% to about 2.55%, and about 5% loss of phenylephrine, calculatedfrom data in a range from about 4.8% to about 5.2% (see Composition 3 inTable 2).

Composition 3 Amount (% w/v) Dextromethorphan HBr 0.20% Guaifenesin4.00% Phenylephrine HCl 0.10% Propylene Glycol 10.00% PolyethyleneGlycol 10.00% Polyvinylpyrrolidone (K-90) 1.00% Citric Acid 0.90%Xanthum Gum 0.10% Menthol 0.02% Glycerin 24.07% FD&C Red #40 0.01%Flavorant 0.80% Sodium Benzoate 0.10% Sodium Citrate 0.20% Sorbitol20.00% Sucralose 0.20% Water q.s.

Composition 3 may be prepared using the manner of preparation describedin Example 2.

Example 4

Composition 4 comprises about 0.5% w/v polyvinylpyrrolidone, about 10%w/v polyethylene glycol and about 10% w/v propylene glycol. Guaifenesinprecipitation was not visible to the naked eye for about 14 days at −20°C. and for at least 62 days at 4° C.

The composition is visually free of guaifenesin precipitation for atleast 62 days at 4° C. and the composition is visually free ofguaifenesin precipitation for 14 days at −20° C. Applicants terminatedtheir visual inspection after 62 days. After Applicants observed visibleprecipitation on the 14^(th) day in the sample composition at −20° C.,Applicants removed the sample composition from the freezer and allowedthe sample composition to warm to room temperature (22° C.). Applicantsvisually observed that all the precipitation in the sample compositionsolubilized back into the solution within 24 hours. No further visualobservations were conducted on the sample composition.

Applicants conducted three stability tests over a 3 month time period at40° C. and 75% relative humidity on three identically prepared samplesof Composition 4. As shown in Table 2, the average degradation of thephenylephrine was observed to be about less than 2% total unspecifiedphenylephrine degradants, calculated from data in a range from about1.59% to about 1.76%, and an average of less than 2% loss ofphenylephrine, more specifically an average of about 1.3% loss ofphenylephrine, calculated from data in a range from about 0.73% to about1.94% (see Composition 4, Table 2).

Composition 4 Amount (% w/v) Dextromethorphan HBr 0.20% Guaifenesin4.00% Phenylephrine HCl 0.10% Propylene Glycol 10.00% PolyethyleneGlycol 10.00% Polyvinylpyrrolidone (K-90) 0.50% Citric Acid 0.90%Xanthum Gum 0.10% Menthol 0.02% Glycerin 24.07% FD&C Red #40 0.01%Flavorant 0.80% Sodium Benzoate 0.10% Sodium Citrate 0.20% Sorbitol20.00% Sucralose 0.20% Water q.s.

Composition 4 may be prepared using the manner of preparation describedin Example 2.

TABLE 1 Number of days with no observed precipitation of guaifenesin at4° C. and at −20° C. Number of days Number of days Composition # with noobserved with no observed (% PVP) precipitation at −20° C. precipitationat 4° C. Composition 1 (0%) 11 50  Composition 2 (2%) 22 62+ Composition3 (1%) 14 45+ Composition 4 (0.5%) 14 62+

Sample compositions were placed in a refrigerator (4° C.) or a freezer(20° C.) and monitored for precipitation once per day. Guaifenesinprecipitation was not visible to the naked eye until the number of daysstated in Table 1 above.

TABLE 2 Average Total Compo- Time at unspecified Average Loss of PEsition 40° C./75% RH phenylephrine (% Initial-% at # (months) (PE)degradants 3 months) 1 Not tested Not tested Not tested 2 3 about 3%about 6% 3 3 about 2% about 5% 4 3 about less than 2% about less than 2%RH = relative humidity % initial = % of phenylephrine (PE) present atinitial testing of newly mixed composition % at 3 months = % ofphenylephrine (PE) present three months after initial testing of newlymixed composition

Although the foregoing invention has been described in some detail byway of illustrations and examples for purposes of clarity ofunderstanding. It will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims. Modificationsof the above-described modes of practicing the invention that areobvious to persons of skill in the art are intended to be includedwithin the scope of the following claims.

The invention claimed is:
 1. A liquid oral pharmaceutical compositioncomprising: i.) from about 0.1% to about 20% w/v polyvinylpyrrolidone;ii.) from about 5% to about 70% w/v polyethylene glycol; iii.) fromabout 1% to about 30% w/v propylene glycol; iv.) from about 1% to 10%w/v guaifenesin; and v.) from about 0.01% to about 1.0% w/vphenylephrine wherein the composition is visually free of guaifenesinprecipitation for at least 62 days at 4° C.
 2. A liquid oralpharmaceutical composition comprising: i.) from about 0.1% to about 20%w/v polyvinylpyrrolidone; ii.) from about 5% to about 70% w/vpolyethylene glycol; iii.) from about 1% to about 30% w/v propyleneglycol; iv.) from about 1% to 10% w/v guaifenesin; and v.) from about0.01% to about 1.0% w/v phenylephrine, further comprising about 4% w/vguaifenesin and about 0.10% w/v phenylephrine, wherein the compositionis visually free of guaifenesin precipitation for 14 days at −20° C. 3.A liquid oral pharmaceutical composition comprising: i.) from about 0.1%to about 20% w/v polyvinylpyrrolidone; ii.) from about 5% to about 70%w/v polyethylene glycol; iii.) from about 1% to about 30% w/v propyleneglycol; iv.) from about 1% to 10% w/v guaifenesin; and v.) from about0.01% to about 1.0% w/v phenylephrine, wherein the composition comprisesabout 4% w/v guaifenesin and about 0.10% w/v phenylephrine, about lessthan 2% total phenylephrine degradants, as a percent weight over weightphenylephrine, and about less than 2% loss of phenylephrine from theinitial total phenylephrine content, measured over a 3 month time periodwhile stored at 40° C. and 75% relative humidity.
 4. A process forpreparing an oral liquid composition, comprising the steps of: a.)mixing until dissolved from about 0.1% to about 20% w/v ofpolyvinylpyrrolidone in an aqueous phase; b.) adding and mixing fromabout 1% to about 20% w/v of at least one pharmaceutical agent; c.)subsequently adding and mixing: i.) water; ii.) from about 1% to about30% w/v of a propylene glycol; iii.) from about 5% to about 70% w/v of apolyethylene glycol; and d.) subsequently adding and mixing one or moreadditional ingredients.
 5. The process of claim 4 wherein thecomposition comprises about less than 2% total phenylephrine degradants,as a percent weight over weight phenylephrine, and about less than 2%loss of phenylephrine from the initial total phenylephrine content,measured over a 3 month time period while stored at 40° C. and 75%relative humidity.
 6. The process of claim 4, wherein the composition isvisually free of guaifenesin precipitation for at least 62 days at 4° C.